Download - MULTIDISCIPLINARY MULTIPLE MYELOMA CARE
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MULTIDISCIPLINARY MULTIPLE MYELOMA CARE
Education Project Overview
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Greatly enhance the education of community providers and adoption of effective practices, including incorporation of the latest and best treatment options for patients diagnosed with multiple myeloma.
I. Raise awareness about education needs of healthcare providers in the community setting related to the management of multiple myeloma patients.
II. Educate the multidisciplinary healthcare team on how to implement effective practices in the treatment of multiple myeloma in community-based programs.
III. Establish vetted and designated resources for multiple myeloma that will be an enduring source of information for providers.
IV. Convene a strong network of advocacy and professional partners to increase peer-to-peer learning and adoption of effective practices.
Project Goals and Objectives
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Site Visits• Yuma Regional Medical Center Cancer Center
• Yuma, Arizona
• Comprehensive Community Cancer Program
• John Theurer Cancer Center at Hackensack University Medical Center
• Hackensack, New Jersey
• Academic Comprehensive Cancer Program
• H. Lee Moffitt Cancer Center
• Tampa, Florida
• NCI-Designated Comprehensive Cancer Program
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International Myeloma Working Group (IMWG)
• Incorporating the latest guidance from the International Myeloma Working Group (IMWG) to improve diagnosis, assess prognosis, and develop tailored treatment plans
• Diagnostic workup that includes flow cytometry,
immunohistochemistry, cytogenetics, and molecular diagnostics
• Revised International Staging System (R-ISS)
• Assess risk profiles and engage in shared decision-making
conversations with each patient
• Refer patients who are eligible candidates for transplant
evaluation
imwg.myeloma.org
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Skeletal-Related Events (SREs)• Many patients with multiple myeloma have bony lesions and are
often treated with either zoledronic acid (infusion) or denosumab (injection)
• Monitor for side effects such as osteonecrosis of the jaw (ONJ)
• Assess patient preferences
• Incorporating the 2018 ASCO Clinical Practice Guideline Update: Role of Bone-Modifying Agents in Multiple Myeloma
• Key clinical question: “What is the role of bone-modifying agents in patients with multiple myeloma?”
• Severe SREs such as spinal cord compression or vertebral compression fractures may occur
• Often requires surgical management to prevent permanent paralysis
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Advancing Research to Improve Care
• John Theurer Cancer Center has been involved with the Multiple Myeloma Research Foundation (MMRF) CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile) Study
• Discovery of 12 different molecular types of multiple myeloma, each with its own level of risk
• Moffitt Cancer Center is a founding member of Oncology Research Information Exchange Network (ORIEN), a cross-institutional research partnership
• Includes a longitudinal study called Total Cancer Care which examines the effects of different cancers, treatment choices, and lifestyle so that physicians can have a better understanding of patient outcomes and treatment options
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Project Webpage
• Advisory Committee
• Educational resources
• Regional lectures and recorded webinars
• Provider Resource Portal
• Journal supplement – Case Studies in Multiple Myeloma Care
accc-cancer.org/multiple-myeloma-care
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MULTIDISCIPLINARY MULTIPLE MYELOMA CARE
Regional Lecture Series
Leveraging a Multidisciplinary Approach to Multiple Myeloma Care
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Leveraging a Multidisciplinary Approach to Multiple Myeloma CareDr. Yogesh S. Jethava, MBBS, FACP University of Iowa Hospitals & Clinics
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Disclosure
•Consultancy: Celgene and Janssen
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Case Scenario
• James Bond, 45-year-old male comes for routine yearly physical
• Found to have elevated total protein
• Further work up: elevated globulins!!
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Case Scenario
• Normal CBC
• Normal Calcium
• Normal Creatinine
• You do specific tests to find out whether this is monoclonal or polyclonal protein• Which are those tests?
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Normal B Cell Development
Travel
Lymph Node
Follicles
BoneMarrow
Pre B cellIgM
B cell
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B Cell Activation
B cell activation
Germinal CenterFormation
“antigen”
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Plasma Cells Travel Back to Bone Marrow
Memory B cell
“Activated B cell”
Plasma Cell
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Properties of Plasma Cells
• Proliferate
• Secrete immunoglobulins
• Influence bone turnover
• Secrete inflammatory mediators
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Common Terminologies
Serum Protein Electrophoresis (SPEP)
Measures the levels of various proteins in the blood and detects abnormal monoclonal
protein level.
Immunofixation (or Immunoelectrophoresis,
IPEP)
This test can reveal the specific type of abnormal protein produced by the myeloma.
Immunoglobulin LevelsActive secretion of one form of
immunoglobulin and suppression of normal immunoglobulin levels.
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Common Terminologies
24-hour urine test for Bence Jones or light chain proteins
in the urine
Actual amount of monoclonal protein secreted by the kidneys.
Serum free light chain measurement
This test measures the amount of light chains in the blood.
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Investigations
• Serum monoclonal protein <3 g/dL
• <10 % bone marrow plasma cells
• Urinary monoclonal protein < 500 mg per 24 hours
• Absence of myeloma defining events or amyloidosis
MGUS
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MGUS
•Does it need treatment? NO
•Does it progress to Myeloma? YES
2% of MGUS per year progress to MM
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Patient is Being Monitored Regularly
• Now he is 50 years of age
• Latest results:• Serum monoclonal protein (IgG or IgA) ≥3 g/dL• Or urinary monoclonal protein ≥500 mg per 24 h • Or clonal bone marrow plasma cells 10–60%• Absence of myeloma defining events or
amyloidosis.
SMOLDERING MYELOMA
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Mr. Bond Wants to Know …
• Which patients will progress early?
• What should we look for?
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Progression to Symptomatic MM
Kyle et al. NEJM, Volume 356:2582-2590, June 21, 2007
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Bone Marrow Plasma Cells
• 21 (3%) had BMPC of 60% or greater
• 95% of these progressed to MM within 2 years of diagnosis
• Median time to progression 7.0 months [95% CI 1.0–12.9])
Larson et al. NEJM, 2012
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Bone Marrow Plasma Cells
• Among 8 (9%) patients with a BM infiltration ≥ 60% all have progressed to symptomatic myeloma and median time to progression to symptomatic disease was 15 months (range from 3 to 56 months)
Kastritis et al. Leukemia (2013) 27, 947–953
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Free Light Chain Ratio
involved/uninvolved FLC ratio of >100
involved/uninvolved FLC ratio of <=100
Larsen et al. Leukemia, 2012
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MRI Lesions
• 23/149 patients had >1 lesion; median TTP not patients with ≤1 FL and 13 months for those with >1 FL
Jens Hillengass et al. JCO 2010;28:1606-1610
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Active (symptomatic) Multiple Myeloma
• HyperCalcemia
• Renal Insufficiency
• Anemia
• Bone Disease
Classical Definition Expanded Definition• BMPC ≥60%
• >1 PET/MRI lesions
• FLC ratio >100
Predicts an 80% or more risk of progression in 2 years
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Current IMWG DefinitionClonal BMPC ≥10% or biopsy-proven plasmacytoma PLUS
- Either a myeloma defining event:
C: Hypercalcemia: serum calcium >1 mg/dL higher than the upper limit of normal or >11 mg/dL
R: Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >2 mg/dL
A: Anemia: hemoglobin >20 g/L below the lower limit of normal, or a hemoglobin <100 g/L
B: Bone lesions: osteolytic lesions on x-ray, CT, or PET-CT
- OR a biomarker of early progression
• Clonal bone marrow plasma cell percentage ≥60%
• Involved: uninvolved serum free light chain ratio ≥100
• >1 focal lesions on MRI studies
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Unique Disease with Precursor Conditions
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Mr. Bond Continues to Follow Up with Your Clinic
• One day, he presents with following symptoms:Back Pain
Fatigue
Anorexia
Recurrent infection
Constipation
Somnolence
Fracture
Neuropathy
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Initial Diagnostic Workup
• H&P
• CBC
• BUN/create.
• Calcium/albumin
• Quant Ig
• SPEP/immunofix.
• Bone marrow biopsy
• 24-hour urine
• UPEP/immunofix.
• Beta2-microglobulin
• Skeletal survey
• PET/MRI
• FISH on BM plasma cells
• Gene expression profiling
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Tests Results!
• Anemia
• Hyper Calcemia
• Renal insufficiency
• Hypogammaglobulinemia
• X-ray: lytic bone lesions
• PET/MRI: focal lesions/extramedullary disease/fractures/ bone damage
• Bone marrow examination and FISH testing
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What Type of Myeloma Do I Have?
• Myeloma is classified by the type of immunoglobulin production
• Immunoglobulins (Ig) are made up of 2 components: light chains and heavy chains
• light chains- kappa or lambda
• Heavy chains- alpha [IgA], gamma [IgG], mu [IgM], delta [IgD], and epsilon [IgE]) chains.
• If there is excess of IgG and kappa, then it is called IgG kappa myeloma
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• Light chain myelomas-• Incomplete immunoglobulin consisting of light chains
only.
• Identified by free light chain assays and urinary free light chain assay.
• Non secretory myeloma occurs in about 1% of myelomas
What Type of Myeloma Do I Have?
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Is this a common disease?
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Age-Adjusted Incidence per 100,000
Male Female
White 6.2 4.1
Black 11.8 10.0
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Etiology
• Familial clustering
• African Americans
• Radiation
• Agriculture, benzene, radiation, sheet metal work
• Chronic inflammatory disorders
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Why do I need PET or MRI? Does it help in treatment?
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Disadvantages of Conventional Radiography
• Reveals lytic disease when over 30% of the trabecular bone has been lost; ~20-30% of patients at diagnosis have normal skeletal survey
• Lack of accurate visualization• Reduced specificity• Observer dependency• Lengthy period for exam• Poor tolerance • Cannot be used for response assessment
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Moulopoulos 2012 AJR
Kusumoto 1997 Br J Haematol
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Usmani S.Z., et al. Blood 2013 Walker R., et al. JCO 2007
PRE-ASCTPOST-ASCT
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PET in MM
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Prognostic Value of PET/CT Before ASCT
Bartel. TB, et al. Blood 2009 Usmani S.Z., et al. Blood 2013
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Prognostic Value of PET/CT Before ASCT
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Myeloma –A Truly Multi-Organ Disease
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Mr. Bond Wants to Know…
• Is this curable cancer? I am just 51 years old! I want to live to see my grandkids!
• What treatment options do I have?
• Triplets: PI, IMiD, and steroid
• Early stem cell transplant
• Sequential transplants (tandem approach)
• Post transplant maintenance
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Multiple Myeloma
Cytopenias
Renal impairment
Neuropathy
Skeletal complications
ThromboembolismPain management
HypercalcemiaAdverse effect of
treatment
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Important to Recognize Skeletal Complications
• 40% of newly diagnosed patients: elevated Alkphos.
• Other tests: • Bone specific alkaline phosphatase • Bone metabolites
• propeptides of type I collagen (P1NP, P1CP) • telopeptides of type I collagen (NTX and CTX)
• levels go down with improved bone health
• Not widely measured on a regular basis
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Supportive Care: Bone Disease
• Vitamin D – > 50 y.o. 800-1000 IU daily
• Measure 25 (OH) D level: <20 ng/ml (50nmol/L) defined as deficient; 21-29 insufficient
• Oral supplementation-
• Ergocalciferol D2
• Cholecalciferol (D3): better at raising 25 (OH) Vit D
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Supportive Care: Bone Disease
• Stop smoking, limit alcohol intake
• Supplements: Institute of Medicine recommends calcium intake, 1200 mg/daily
• EXERCISE IS KEY!
• Movement, 30 min daily: walking, dancing, tai chi, weight training, PT
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Bisphosphonates: Duration
• Bisphosphonates recommended for all patients with lytic bone disease, monthly for 24 months
• Restart at time of relapse
• After two years of continuous use, unclear what should be recommended
• ?
• Every 3 - 6 months
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Bisphosphonates: Duration
• In patients who do not have active myeloma and are on maintenance therapy, the physician may consider a 3-monthly bisphosphonate administration.
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Bisphosphonates: Monitoring
• Creatinine should be monitored before each dose of pamidronate or zoledronic acid
• 24 hr. urine albumin: ideal tests
• > 500 mg/24 hours of urinary albumin - discontinue bisphosphonates
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Bisphosphonates: Monitoring
• If renal deterioration, hold zoledronic acid or pamidronate
• Resume bisphosphonates at the same dosage when serum creatinine returns to within 10% of the baseline level
• Monitor serum calcium and vitamin D levels regularly
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Xgeva
• Xgeva inhibits the RANK ligand mediated osteoclastic over activity
• Does not require monitoring of renal function
• More pronounced hypocalcemia
• Should not be stopped abruptly
• Contraindicated in HypoCa: check Ca levels
• Jaw problems can happen!
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Should I consider early transplant in MM?• Absolutely, yes!
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Clonal Tiding Over Multiple Treatment Relapse Cycles:
Keats JJ, et al. Blood. 2012;120:1067-76.
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No heterogeneity
All myeloma cells are the same
Intraclonal heterogeneity
Different MM clones sharing features
Interclonal heterogeneity
Different MM clones NOT sharing features
Intraclonal Heterogeneity
.
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Why does disease keep relapsing?
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Composition of Residual Clonal Populations
Post-Induction Chemotherapy
Most resistant clones
1 2
3
Resistant Out of Cycle
Cure/eradicate proliferating clones
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Minimal Residual Disease (MRD)
• In MM, MRD describes detectable malignant cells that remain after treatment; these indicate a remaining tumor burden, even in the presence of confirmed response1
• MRD can be present in patients who achieved a CR2,3
• These remaining malignant cells can contribute to relapse4
1. Kumar S et al. Lancet Oncol. 2016;17(8):e328-e346. 2. Paiva B et al. Blood. 2008;112(10):4017-4023. 3. Rawstron AC et al. J Clin Oncol. 2013;31(20):2540-2547. 4. Martinez-Lopez J et al. Blood. 2014;123(20):3073-3079. 5. Paiva et al. Blood. 2015;125(20):3059-3068.
Malignant Cells
109 Presentation
108
107
106
105
104
103
102
101
1
0
CR
VGPR
PR
sCR
MRD
Undetectable MRD
Operational Cure
Depth of Response as Measured by Remaining
Malignant Cells5
Republished with permission of American Society of Hematology, from Paiva et al. Blood. 2015;125(20):3059-3068; via Copyright Clearance Center, Inc.
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MRD Is Associated with Improved Patient Outcomes
• Measurement of MRD is used to qualify increasingly robust or deep responses that are observed with novel agents and combination treatment1-3
• MRD is associated with longer OS in newly diagnosed patients2,3
• MRD vs. MRD+ status is associated with longer OS and TTP3 in patients who achieved CR
TTP = time to progression.*In 133 patients included in the GEM clinical trials. Patients <65 years were treated within the GEM2000 or GEM05 <65 protocols, whereas elderly patients were treated within the GEM05 ≥65 or GEM10 ≥65 trials. Patients were newly diagnosed and had untreated symptomatic MM.3-6
1. Kumar S et al. Lancet Oncol. 2016;17(8):e328-e346. 2. Landgren O et al. Bone Marrow Transplant. 2016;51(12):1565-1568. 3. Martinez-Lopez J et al. Blood. 2014;123(20):3073-3079. 4. Lahuerta JJ et al. J Clin Oncol. 2008;26(35):5775-5782. 5. Mateos MV et al. Lancet Oncol. 2010;11(10):934-941. 6. Rosiñol L et al. Blood. 2012;120(8):1589-1596.alig
Impact of MRD status on survival and time to progression3*
P=0.0009.
100
80
60
40
20
0
0 50 100 150
Months
TTP
, %
MRD-, n=26MRD+, n=36threshold: 10-5
CR patients:100
80
60
40
20
0
0 50 100 150
Months
Surv
ival
, %
P=0.02.
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Newer Approaches
BCMA = B-cell maturation antigen; SLAMF7 = signaling lymphocytic activation molecule family member 7; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death ligand 1.
1. Feyler S et al. Blood Rev. 2013;27(3):155-164. 2. Tai UT et al. Blood. 2016;127(25):3225-3236. 3. Krejcik J et al. Blood. 2016;128(3):384-394. 4. Hsi ED et al. Clin Cancer Res. 2008;14(9):2775-2784. 5. Cruz-Munoz ME et al. Nat Immunol. 2009;10(3):297-305. 6. Hallet WH et al. Biol Blood Marrow Transplant. 2011;17(8):1133-1145.
Approaches that address immune suppression in MM may allow the patient’s
own immune system to identify and eradicate cancer cells1
Several proteins relevant to suppressive or effector immune cells have demonstrated therapeutic utility or are being
investigated as targets for the treatment of MM2-6
BCMAExpressed by MM cells; implicated in the expression of
immunosuppressive molecules2
CD38Expressed by MM
cells and subsets of
immune suppressive cells3
SLAMF7Expressed by MM
cells; also functions as an activating receptor
for NK cells4,5
PD-1/PD-L1PD-1 and its ligand PD-L1 are overexpressed in MM and contribute
to suppression of effector T-cell
responses6
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Closing Thoughts
• MGUS/Smoldering needs regular follow-up
• FISH/MRI or PET at diagnosis
• Early ASCT
• MRD negativity - important
• Post ASCT maintenance
• New options available!
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Questions?
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Thank You!